The Balance of Safety, Efficacy, and Reasonable Assurance in DES An FDA View

Transcription

1 The Balance of Safety, Efficacy, and Reasonable Assurance in DES An FDA View Elizabeth Hillebrenner, MSE Interventional Cardiology Devices Branch Office of Device Evaluation Center for Devices and Radiological Health U.S. Food and Drug Administration

2 Disclosure Information The Balance of Safety, Efficacy, and Reasonable Assurance in DES An FDA View Elizabeth Hillebrenner Nothing to disclose

3 Outline Regulatory definitions Preclinical evaluations Clinical evaluations RCT vs single arm Comparators Endpoints Sample size Follow-up duration Post-market considerations Myths and misperceptions

4 a reasonable assurance of safety and effectiveness Safety: when it can be determined based on valid scientific evidence that the probable benefits to health from use of the device for its intended uses and conditions of use, when accompanied by adequate directions and warnings against unsafe use, outweigh the probable risks. (21 CFR 860.7)

5 a reasonable assurance of safety and effectiveness Effectiveness: when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results. (21 CFR 860.7)

6 Preclinical Evaluation Biocompatibility Functional testing Includes long term fatigue Computational modeling Drug safety studies Animal studies

7 Clinical Evaluation Trial design affected by new -ness of DES Drug NME (new molecular entity) approved but not for intravascular use, or in significantly different dose/concentration Used in current DES (paclitaxel, sirolimus, everolimus, zotarolimus) Stent platform Stent material (316L, CoCr, new alloy) Stent design (strut thickness, surface area) Drug release Drug release profile, mechanism and/or carrier (polymer) Manufacturing parameters

8 How new is the DES? DES A DES B DES C drug NME Approved for systemic indication paclitaxel sirolimus stent New stent material 316L, CoCr, nitinol platform approved stent platform drug release Novel drug release mechanism Similar drug release profile (local/systemic) Same drug release mechanism/profile as approved DES Entirely New Product New and old technologies Serial Iteration of existing DES HHS/FDA/CDRH

9 Clinical Evaluation Trial Design RCT vs. single-arm study RCT recommended for initial marketing approval Single-arm studies may be appropriate for Minor product modifications Addition of new stent sizes, lengths Some indication expansion

10 Clinical Evaluation Trial Design Given prevalence of DES use, noninferiority studies using active DES controls are the current paradigm of study design Choice of delta for equivalency must be clinically meaningful Concern for outcome drift in successive noninferiority studies

11 Clinical Evaluation Trial Design Primary endpoint of Target Lesion Failure CV death, target vessel MI, target lesion revascularization Clinical composite of safety and effectiveness Strong consensus exists that all components are clinically important and expected to trend in the same direction All individual components analyzed as key secondary endpoints May be underpowered to test for statistical differences in components Prespecified hypotheses and adjustments for multiplicity are needed to demonstrate statistical significance

12 Clinical Evaluation Trial Design Angiographic endpoints Examples: In segment late loss % diameter stenosis Binary restenosis rate Provide important mechanistic insights Inhibition of neointimal proliferation Mal-apposition Positive remodeling Not adequate to demonstrate safety

13 Clinical Evaluation Trial Design For DES with NMEs and degradable stents, sample size driven by safety considerations Ability to detect catastrophic safety events that occur at a 1% rate with an upper 95% confidence bound of 1.4% Corresponds to at least 2000 patients Not all patients need to be part of a randomized trial Can use multiple trials (both US and OUS) to achieve this cohort

14 Clinical Evaluation Trial Design Length of follow-up Current recommendations: 12 month primary endpoint collection 5 years follow-up Recommendations may change for: Biodegradable polymer or totally bioabsorbable stents Drug that elutes over longer period of time or stays resident in arterial tissue for longer period

15 CDRH s Total Product Life Cycle Approach

16 Post-Approval Studies FDA requests additional 2000 patient post-approval registries (single arm) to collect outcomes from realworld patients treated with new product Potential to pool data with premarket studies to increase precision around point estimates of safety outcomes (cardiac death and MI) Enroll more complex lesions and patients Bifurcation lesions Long lesions Small diameter arteries Chronic occlusions AMI patients Multivessel disease

17 Myths and Misconceptions about FDA FDA wants to stifle development Our mission is to get good products to patients who need them FDA does not require absolute safety and effectiveness our standard is a reasonable assurance Effectiveness vs. performance Balance between getting new treatments to patients and our mandate to protect the public health

18 Myths and Misconceptions FDA is a black box about FDA We aim to make our decisions transparent Summary of Safety and Effectiveness Data Advisory Panel meetings Dispute Resolution Guidance documents Transparency initiative in CDRH s Strategic Plan We encourage interaction With manufacturers With professional societies With academic clinicians With regulatory agencies in other countries

19 Myths and Misconceptions about FDA FDA sees other countries as an incubator for US device development FDA seeks a global approach to device development Global trials are often feasible and advantageous Efficient use of data collected both US and OUS for regulatory and reimbursement purposes We can assist with approaches to data poolability Global approach moves good devices to patients faster

20 Acknowledgement This presentation reflects collaboration with ICDB Branch Chief Ashley Boam and Medical Officer Andrew Farb, MD.

21 Thank you! Contact information: